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Neuroglia Infection by Rabies Virus After Anterograde Virus Spread in Peripheral Neurons

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Neuroglia Infection by Rabies Virus After Anterograde Virus Spread in Peripheral Neurons bioRxiv preprint doi: https://doi.org/10.1101/2020.09.20.305078; this version posted September 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Neuroglia Infection by Rabies Virus after Anterograde Virus Spread in Peripheral Neurons 2 3 Madlin Potratz, Luca M. Zaeck, Carlotta Weigel, Antonia Klein, Conrad M. Freuling, Thomas Müller, Stefan 4 Finke* 5 Friedrich-Loeffler-Institut (FLI), Federal Research Institute for Animal Health, Institute of Molecular Virology 6 and Cell Biology, 17493 Greifswald-Insel Riems, Germany 7 8 9 10 * Correspondence: [email protected]; Tel.: +49-38351-71283; Fax.: +49-38351-71151 11 12 13 14 15 16 Keywords: rabies pathology, tissue optical clearing, 3D tissue imaging, light sheet microscopy, neuroglia 17 infection, Schwann cell 18 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.20.305078; this version posted September 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 19 Abstract 20 The highly neurotropic rabies virus (RABV) enters peripheral neurons at axon termini and requires long distance 21 axonal transport and trans-synaptic spread between neurons for the infection of the central nervous system (CNS). 22 Whereas laboratory strains are almost exclusively detected in neurons, recent 3D imaging of field RABV-infected 23 brains revealed an remarkably high proportion of infected astroglia, indicating that in contrast to attenuated lab 24 strains highly virulent field viruses are able to suppress astrocyte mediated innate immune responses and virus 25 elimination pathways. While fundamental for CNS invasion, in vivo field RABV spread and tropism in peripheral 26 tissues is understudied. Here, we used three-dimensional light sheet and confocal laser scanning microscopy to 27 investigate the in vivo distribution patterns of a field RABV clone in cleared high-volume tissue samples after 28 infection via a natural (intramuscular; hind leg) and an artificial (intracranial) inoculation route. Immunostaining 29 of virus and host markers provided a comprehensive overview of RABV infection in the CNS and peripheral 30 nerves after centripetal and centrifugal virus spread. Importantly, we identified non-neuronal, axon-ensheathing 31 neuroglia (Schwann cells, SCs) in peripheral nerves of the hind leg and facial regions as a target cell population 32 of field RABV. This suggest that virus release from axons and infected SCs is part of the RABV in vivo cycle and 33 may affect RABV-related demyelination of peripheral neurons and local innate immune responses. Detection of 34 RABV in axon surrounding myelinating SCs after i.c. infection further provided evidence for anterograde spread 35 of RABV, highlighting that RABV axonal transport and spread of infectious virus in peripheral nerves is not 36 exclusively retrograde. Our data support a new model in which, comparable to CNS neuroglia, SC infection in 37 peripheral nerves suppresses glia-mediated innate immunity and delays antiviral host responses required for 38 successful transport from the peripheral infection sites to the brain. 39 40 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.20.305078; this version posted September 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 41 Introduction 42 Rabies is estimated to cause 59.000 human deaths annually in over 150 countries, with 95% of cases occurring in 43 Africa and Asia (reviewed in [26,21]). The disease is caused by a plethora of highly neurotropic, non-segmented, 44 single-stranded RNA viruses of negative polarity belonging to the family Rhabdoviridae of the order 45 Mononegavirales, of which the rabies virus (RABV) is the type species of the Lyssavirus genus [2]. RABV and 46 other lyssaviruses enter the nervous system at the synapses of peripheral neurons. After receptor-mediated 47 endocytosis, the virions remain in endosomal vesicles and hijack the retrograde axonal transport machinery 48 [33,23,59] to reach the neuron soma, where virus ribonucleoproteins (RNPs) are released into the cytoplasm [47] 49 for virus gene expression and replication. Newly formed virus is then transported to post-synaptic membranes, 50 followed by trans-synaptic spread to connected neurons [12]. Prolonged replication of pathogenic RABV in the 51 brain eventually leads to the onset of a progressive rabies encephalitis, invariably resulting in the fatal disease 52 progression. In animals suffering from RABV encephalitis, the virus can be detected in multiple nervous or 53 innervated tissues including hind leg, spinal cord, brain, face, and salivary glands [5,15]. For the transmission of 54 infectious virus to new hosts via virus-containing saliva, centrifugal spread of RABV in the peripheral nervous 55 system (PNS) is required [18]. The secretion of RABV-containing saliva by salivary glands is commonly accepted 56 as the main source of virus shedding and virus transmission to uninfected animals via bites (reviewed in [21,16]). 57 Detection of RABV in sensory neurons of the olfactory epithelium and other tissues during late stages of infection 58 indicates that, at least in these late phases of disease, the axonal transport is not exclusively retrograde (reviewed 59 in [16]). In fact, studies have shown that RABV enters the anterograde axonal transport pathway in cultivated 60 primary rat dorsal root ganglion (DRG) neurons [6] and in mice [70]. However, the consequences of anterograde 61 transport of RABV is still controversially discussed, even though infection through intradermal sensory neurons 62 represents a likely route of entry for lyssaviruses as a result from bat bites [7]. 63 Because of their trans-synaptic spread, RABVs constitute ideal viruses to map neuronal connections [67,66] as 64 even attenuated RABVs enter axonal transport pathways [33]. More neuroinvasive yet still lab-adapted strains like 65 CVS-11 have been used as polysynaptic neuron tracers and the resultant insights have subsequently been used to 66 explain in vivo RABV spread and pathogenesis [61]. However, already between different CVS strains, substantial 67 differences in pathogenicity exist [39], raising the question whether knowledge from established lab-adapted 68 strains can be extrapolated to explain actual field RABV infection and pathogenesis. 69 The advent of efficient full-genome cloning techniques opened novel avenues for the analysis of virus variability 70 in combination with phenotypical characterization of recombinant field viruses at a clonal level [43]. For example, 71 a recent comparison of field and lab RABV clones in mice revealed that field viruses not only showed a higher 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.20.305078; this version posted September 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 72 virulence compared to lab strains such as CVS-11 but also substantially differ in their ability to establish infection 73 in non-neuronal astroglia in the central nervous system (CNS) [48]. In contrast to attenuated lab-adapted RABV, 74 which is supposed to be eliminated from infected glial cells (astrocytes) by type I interferon-induced immune 75 reactions [46], it has been hypothesized that rapid onset of field virus gene expression in non-neuronal astrocytes 76 blocks inhibitory innate immune activation and responses [48]. This may not only affect RABV replication in glial 77 cells directly but also in surrounding neurons via paracrine signalling. Thus, this mechanism may be crucial to 78 RABV spread and pathogenesis in vivo. Apart from astrocytes, in vivo infection of non-neuronal muscle, 79 epidermal, and epithelial cells have been described [12,5,13,42]. In foxes, which had been orally immunized with 80 live-attenuated RABV, infected cells can be detected in the epithelium of lymphoid tonsils [63,56]. In vitro, even 81 immature DCs or monocytes can be infected [35]. Overall, knowledge on the broad spectrum infection pattern of 82 RABV in vivo, particularly of field RABV strains, is still incomplete and the identification of PNS and non- 83 neuronal cells involved in RABV spread and pathogenesis has been given little attention. 84 Therefore, by using a highly virulent field RABV clone of dog origin (rRABV Dog) [43], we set out to 85 systematically and comprehensively elucidate the in vivo spread and cell tropism of a field RABV strain. So far, 86 technical limitations in conventional histology to visualize infection processes in complex tissues in large three- 87 dimensional (3D) volumes at a mesoscopic scale and high resolution hindered a comprehensive overview of RABV 88 cell tropism, in vivo spread, and pathogenesis. Immunofluorescence-compatible tissue clearing iDISCO and 89 uDISCO (immunolabeling-enabled and ultimate three-dimensional imaging of solvent-cleared organs, 90 respectively) protocols [45,49] recently allowed us to perform high-resolutions 3D immunofluorescence analyses 91 of thick RABV-infected tissues slices [69,48]. 92 Here, we investigated the in vivo spread of a highly virulent field RABV clone (rRABV Dog) through the CNS 93 and PNS after intramuscular (i.m.) and intracranial (i.c.) inoculation. Using 3D immunofluorescence imaging of 94 solvent-cleared tissues by light sheet and confocal laser scanning microscopy, we identified RABV infections in 95 hind leg nerves, spinal cord, brain, and nerves of the facial region.
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